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Multimodal characterisation of the SMN locus in SMA: copy number quantification and hybrid gene identification

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • González-Alvaredo, S
  • Lesende, I
  • Onsurbe, I
  • Millán, JM

Grupos

Abstract

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic disruption of the Survival Motor Neuron 1 (SMN1) gene. Accurate quantification of Survival Motor Neuron 2 (SMN2) copy number is essential for patient stratification, prognosis, and treatment decisions, yet remains challenging at high copy numbers and does not fully explain phenotypic variability. We compared complementary molecular approaches in 78 Spanish patients with genetically confirmed SMA. Multiplex ligation-dependent probe amplification (MLPA) and digital PCR (dPCR) showed complete concordance, supporting their reliability for SMN2 quantification. In contrast, the AmplideX PCR/CE SMN1/2 Plus Kit showed discrepancies in seven patients, mainly at clinically relevant thresholds (three vs. four SMN2 copies), indicating higher sensitivity to technical variability. Notably, dPCR resolved a case with >5 SMN2 copies, demonstrating superior resolution. Long-read sequencing (LRS) in ten patients with MLPA-detected rearrangements enabled high-resolution reconstruction of the SMN locus and revealed six previously undescribed SMN hybrid structures. Structural haplotype architecture, rather than copy number alone, may further determine SMN variability and contribute to phenotype heterogeneity. Overall, our findings support an integrated diagnostic strategy in which copy-number quantification is complemented by structural characterisation in complex cases, improving molecular resolution of the SMN locus.

Datos de la publicación

ISSN/ISSNe:
2056-7944, 2056-7944

npj Genomic Medicine  NATURE PORTFOLIO

Tipo:
Article
Páginas:
-
PubMed:
42162012
Factor de Impacto:
2,111 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 1

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